When does a cell decide which direction to take?

Overview of the initiation of differentiation in hESCs. Early G1 phase directs cells into endoderm and mesoderm whereas neuroectoderm is blocked. Late G1 phase directs cells into neuroectoderm whereas endoderm and mesoderm is blocked.
[DOI: 10.1016/j.cell.2013.08.031]

New cells used in growth or for repair of a damaged tissue derive from a group of specialised dividing cells - stem
cells. Stem cells can divide to maintain the source of new cells or can commit irrevocably to becoming a specialised
cell, such as a liver or pancreas cell.

Now, researchers describe for the first time the switches that determine how stem cells make that crucial decision.
Their work might enable stem cells to be converted into a range of adult tissues more efficiently and more
homogeneously.

Pluripotent stem cells have the potential to become any cell in the body. Interest in them has grown with the hope that
they might be used to replace dying or damaged cells with healthy cells. Repairing tissues would be important in organ
regeneration, bone repair and treatment of neurodegenerative diseases.

The team looked at the activity of key genes and proteins during the cell cycle - the processes by which a cell divides
- in human pluripotent stem cells. They found that the molecular decision to continue to divide or to differentiate -
to commit to a pathway towards a defined tissue type - is made during a restricted phase of the cell cycle.

"We know that cell division and differentiation need to be interconnected, but the mechanisms
involved are yet to be uncovered," says Dr Ludovic Vallier, lead author from the Wellcome Trust Sanger Institute
and the University of Cambridge. "For the first time, we have a glimpse of how these two processes
are biologically linked."

" For the first time, we have a glimpse of how cell division and differentiation are biologically linked. "

Dr Ludovic Vallier

"We have found key regulators of this process and have new methods that could more efficiently produce cell types with
a clinical interest from human pluripotent stem cells."

They looked at the times during the cell cycle that the stem cell could commit to specific lineages, including liver
and pancreas. They found that the decision could be made only at certain stages of the cell cycle and that the timing
of the decision could drive the cell down different pathways.

This potential synchronisation of stem cells could result in new methods to generate specific cell types for
regenerative medicine.

The team showed that these cell-cycle restricted decisions are influenced by a group of proteins known as cyclin Ds.
The activity of these proteins, which control cell cycle progression, only direct the differentiation of human
embroyonic stem cells toward specific lineages by controlling external stimuli. It is possible that the cyclin D
mechanisms the team found in human stem cells work in a similar way during the development of human organs and in the
natural repair or regrowth of tissues in adults.

The researchers also found that they could use a simple chemical compound, rather than a protein, to drive the stem
cells towards tissues such as the liver. Modifying the activity of cell cycle regulators with simpler chemical
treatments could make stem cell differentiation more efficient in the future.

"We have to uncover the biological secrets of stem cell biology to realise fully their
value," says Professor Mike Stratton, Director of the Wellcome Trust Sanger Institute. "This
work helps us to understand how a stem cell makes a key decision - whether to divide and remain a stem cell, or to
enter on a pathway to contributing to tissue, as we would require for regenerative medicine.

"With this knowledge, Dr Vallier and his colleagues will be able to refine the methods that help stem cells to become,
for example, pancreas or liver cells."

Notes to Editors

Publication details

The cell-cycle state of stem cells determines cell fate propensity.

Funding

The work was funded by Medical Research Council and the Cambridge Hospitals National Institute for Health Research
Biomedical Research Center.

Participating Centres

Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Laboratory for Regenerative Medicine and
Department of Surgery, University of Cambridge, Cambridge, UK

Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

Medical Research Council

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supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize
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